Derivative of alpha, gamme-dihydroxy-beta, beta-dimethyl-butyric acid and process for the manufacture of same



Patented May 29, 1945 UNITED STAT DERIVATIVE OF METHYL-BUTYRIC ACID AND PROCESS FOR THE MANUFACTURE OF SAME Tadeus Reichstein, Basel, Switzerland, assiznor I to Hoi'fmann-La Roche Inc., Nutley, N. J a corporation of New Jersey No Drawing. Application May 29, 1944, Serial No. 537,978. In Switzerland September 6, 1943 4 Claims.

It has been found that a new derivative of d() -a,'y-dihydrOXy as dimethyl-butyric acid can be obtained if 3,4 dihydroxy-butyiamine or dimethyl-methylene-3,4-dihydroxy-butylamine is caused to act on a-hydroxy-dp-dimethyl- -butyric-acid-lactone. In the latter case, the resulting condensation product must be subjected to a gentle, acid hydrolysis. This reaction proceeds according to the following formulae:

In this reaction it is surprising that it is possible to split 01! the acetone radical tom the condensation product without destroying the amide-link- ,age, because pantothenic acid as well' as the hydroxy alkyl amides of a,'y-dihydroxy-p,fl-dimethyl-butyric acid are extraordinarily easily saponifiable in comparison with other acid amides. The optical acitvity is not influenced by the hyfiolysis.

The 3,4- (dimethyl-methylene-dihydroxy) -butylamine (II) needed as starting material can be prepared in the following manner: delta-hy- Y tity of methanol saturated at 0 C. with dry NHa.

The said 4,5-dihydroxy-valeric-acid-amide, obtained as a colourless, viscous oil, is thereupon dissolved in about 100 parts by weight 02 dry acesoluble.

tone. Then a little dry hydrochloric acid gas is introduced until the solution just reacts acid to Congo paper. After standing for one day, it is shaken witha little solid potassium carbonate, flitered and evaporated. The residual 3,4- (dimethylmethylene-dihydroxy) -valeric-acid-amide can be distilled in vacuo at 0.1 mm. under C. and crystallised from acetone-ether in small colorless plates of melting point 92 C. The decomposition oi this amide in accordance with Hofmann yields the required base (11), which boils in a vacuum 0t 11 mmat 74-75" C. as a very mobile, colorless liquid and which easily absorbs 002 as well as water from the air. It yields a picrate melting at 157-l58 C.

For condensation purposes, the 3,4-(dimethylmethylene-dihydroxy) -butylamine is reacted with the equimolecular quantity of d(-)-u-hydroxy- 43,;8-dimethyl- -butyrolactone, preferably in an indiflerent solvent in which both components are The reaction already occurs at room temperature after about 24 hours and can be accelerated by heating. The 3,4-(dimethyl-methylene-dihyclroxy) -butylamide of an! dihydoxypfi-dimethyl-butyric acid thus obtained forms a colorless oil which can be distilled in high vacuo without decomposition. Under a pressure of 0.1 mm., the compound distills at a bath-temperature of about C.

a,'y-Dihydroxy-fl,fldimethyl-butyric acid 3, i-(dimethyl-methylene-dihydroxy) butylamine (III), when subjected to a mild, acid hydrolysis, yields 3,4-dihydroxy butylamide of d-a,-y-dihy' droxy-p,,B-dimethyl-butyric acid (IV) as a colorless, hygroscopic, very viscous and easily watersoluble oil, which, even in vacuo, cannot be distilled without decomposition. Its analytical figures correspond to the formula CmHnOsN.

Example 1 A solution of 10.5 parts by weight of 3,4-dihydroxy-butylamine in 20 parts by volume of methanol, prepared under exclusion of water and carhon-dioxide, is treated with- 13 parts by weight of dry d'() -a-hydroxy-p,p-dimethyl-y-butyricacid-lactone, which readily goes into solution. The mixture is then allowed to stand for 24 hours in a closed receptacle or boiled under reflux for one hour. The methyl-alcohol is thereupon distilled ofi and the residue dried in high vacuo at 120 C. The d(+) -a,q-dihydroxy-p,c-dimethylbutyric-acid-3',4'-dihydroxy-butylamide thus obtained in almost theoretical yield is a viscous, nearly colorless oil readily soluble in water.

Example 2 V 2 by weight of dJ-dlmethyl-methylene- 3,4-dihydroxy-butylamine and 1.7 parts by weight or d( -a-hydroxy-p,p-dimethyi-v-butyric-acidlactone are dissolved in 12 parts by weight of anhydrous benzene and the solution boiled under reflux for one hour under exclusion of moisture. The solution is then evaporated to dryness in vacuo.

For the subsequent working up. a further purification is not necessary, although it is possible to distill the com ound at a pressure of 0.1 mm. When analysing the distillation product, figures corresponding to the theory are obtained for carbon, hydrogen and nitrogen.

7 parts by weight of the crude condensation product are dissolved in 50 parts by volume of n/l sulfuric acid and left to stand at 18 C. By determination of the split-01f acetone it can be proved that under these conditions the saponification has come to an end after 30 minutes. The solution is neutralised by means of stirring in an excess of freshly precipitated barium-carbonate and passed through a suction filter cov- I ered with alayer of barium-carbonate and a litdron-butyD-amide, which remains behind in vacuo upon concentration of the solution.

I claim:

1. A derivative of a,'y-dihydoxy-p,,a-dimethylbutyric acid, consisting of d(+)-2,4-dihydroxy- 3,3-dimethyl-butyric-acid r (3',4'-dihydroxy butyl) amide.

2. Process for the manufacture of a derivative of 1, dihydroxy-p,p-dimethyl-butyric acid, comprising cdndensing d(-) -a-hydroxy-fl,p-dimethyl-v-butyric-acid-lactone with a substance selected from the group consisting of 3,4-dihydroxybutylamine and the dimethyl-methylene derivative thereof. I

3. Process for the manufacture of a derivative of a, -dihydroxy-p,p-dimethyl-butyric acid, comprising condensing d()-a-hydroxy-p,fl-dimethlyl-y-butyric-acid-lactone with 3,4-dihydroxy-butylamine in the presence of a solvent.

4. Process for the manufacture of a derivative of an-dihydroxy-ap-dimethyl-butyric acid, comprising condensing d(-) -a-hydroxy-fi,fi-dimethyl-y-butyric acid lactone with d,l dimethylmethylene-3,4-dihydroxy butylamine and subjecting the condensation product obtained to a mild, acid hydrolysis.

TADEUS REICHSTEIN. 

